It is well recognized that pharmacologic estrogen administration (hormone replacement therapy, HRT) can alleviate most, if not all, of the symptomology associated with the menopause. These symptoms include, but are not limited to: bone loss associated with osteoporosis; heart disease associated with changes in blood lipids and lipoproteins; hot flashes; and vaginal dyspareunia.1 However, there are risks associated with estrogen administration in HRT as well as oral contraceptive use, and include an association with endometrial cancer, breast cancer, and stroke. Although for the most part, the therapeutic benefits of HRT outweigh the risks, nevertheless, while the risks are small, they do exist.2-4 
Estrogen therapy, directly and indirectly, affects a number of organs. Some of the outcomes associated with estrogen therapy are deleterious. Consequently, where possible, symptomology which could be ameliorated by local rather than systemic administration could limit the adverse side-effects of estrogen therapy. One such syndrome that can be treated directly, caused by estrogen deprivation or estrogen antagonists, is vaginal dyspareunia. It is a common disorder which affects a large proportion of women, approximately 40% within 10 years of the onset of the menopause.5 It is an important factor in the quality of life for women so afflicted, as it is associated with a severe physical and psychological impact. It is not only painful but it can dramatically influence a women's self image and lead to clinical depression.6 Another possible use of local estrogens includes topical administration to aging skin. The skin contains ER and it is an estrogen target organ.7-9 While topical application of estrogens to the vaginal mucosa has been used to treat vaginal dyspareunia of the menopause, these estrogens are adsorbed into the blood and result in significant blood levels of estrogens.10-13 Thus, this therapy may not be used where systemic estrogens are contraindicated.
Since topically applied estrogen is adsorbed into the blood, its purpose is defeated. A potent estrogen whose range is limited to the tissue to which it is applied would be ideal for the treatment of these disorders. Similar therapeutic agents with locally limited actions have been termed “soft drugs”14, compounds which have a limited region of activity due to rapid metabolic inactivation. Ester groups have been used to convey “soft drug” properties to biologically active molecules because hydrolytic enzymes, including esterases, are ubiquitously distributed.15 The ester containing compounds are the active agents while their hydrolysis products, the carboxylic acids, are inactive. In this manner, locally active glucocorticoids have been developed as antiinflammatory agents for the skin. These are esters of steroids substituted with a carboxylic acid group. The parent carboxylic acids do not bind to the glucocorticoid receptor and are biologically inert while their corresponding esters bind to the glucocorticoid receptor with high affinity.16,17, The esters are rapidly hydrolyzed to the parent steroidal-carboxylic acid and thus, are inactivated by the ubiquitous esterases. Consequently, they can be used as anti-inflammatory agents for skin because their action is localized to the area to which they were applied, i.e., their rapid inactivation prevents systemic action.18 
Similarly, in a study designed to produce affinity chromatographic supports for the purification of the estrogen receptor (ER) it was found that carboxylic acid analogs of estradiol (E2) at C-7α- and C-17α are very poor ligands if they bind at all, but the methyl esters of these same analogs have much improved affinity for the ER.19 It appears from those results that a charged carboxylic acid group in proximity to the steroid ring interferes with binding to the ER and that masking the charge by esterification reverses this interference.
In order to synthesize a locally active estrogen we previously described a series of compounds in which analogs of estradiol (E2) were modified at 16α-with a series of carboxylic esters to produce a locally active estrogen that could be applied directly into and act solely within the vagina, without producing systemic effect.20 Our design for a locally active estrogen is based upon the synthesis of analogs of estradiol containing carboxylates in proximity to the steroid nucleus. These organic acids have poor affinity for the estrogen receptor while esters of these same carboxylic acids bind very well to this receptor20. To be restricted to local action, these potent estrogens would be rapidly inactivated by esterases. The 16α-carboxylates of E2 that we described were designed and tested for the following characteristics: affinity for the estrogen receptor; biological activity in an in vitro estrogen sensitive model (endometrial cells in culture); as substrates for esterase hydrolysis; local action through in vivo estrogenic stimulation of the vagina; systemic activity (uterotrophic action). Two of these E2-analogs, the ethyl and 2′-monofluorethyl esters of E2-16α-formate showed the requisite properties with significant differences in their systemic and local actions. Our aim in the present study was to design a second generation of local estrogens with increased estrogenic potency leading to greater local action and yet decreased systemic action. To this end we synthesized carboxylic esters of estradiol at 15α, at which substituents are known to be tolerated by the estrogen receptor.21 These esters and carboxylic acids were tested for estrogenic potential (binding to the estrogen receptor; in vitro bioassay; in vivo, vaginal and uterotrophic assays) and as substrates for esterase enzyme(s).